Verquvo
vericiguat
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Why that species
Mouse, rat and dog most relevant species on pharmacokinetic grounds
“From the pharmacokinetic point of view, mouse, rat and dog were the most relevant species for non-clinical efficacy and safety studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeated dose toxicity studies were conducted up to 13 weeks in mice, up to 6 months in rats, and 39 weeks in dogs.”
Species: general tox
Rat (6-month) and dog (39-week)
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“in reproductive and developmental toxicity studies (including embryo-fetal development studies in rats and rabbits, fertility and early embryonic development and a pre- and postnatal development study in rats, and juvenile toxicity studies in rats)”
Species: carcinogenicity
CD1 mouse and Wistar rat (2-year)
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
Surrogate used in
No surrogate used; vericiguat tested directly in mouse, rat and dog
“Repeated dose toxicity studies were conducted up to 13 weeks in mice, up to 6 months in rats, and 39 weeks in dogs.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Pivotal GLP studies
6-month rat and 39-week dog oral GLP studies
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Route in tox
Oral
“The pivotal studies were conducted in accordance with GLP guidelines and used the oral route of administration, consistent with the clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat and mouse micronucleus assays
“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”
Carcinogenicity
2-year CD1 mouse and Wistar rat: not carcinogenic
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats. Vericiguat did not show a carcinogenic effect in mice dosed up to 150 mg/kg/day (males) or up to 250 mg/kg/day (females).”
Reproductive & developmental
Rabbit EFD: cardiac ventricular septal defect and truncus arteriosus at ≥2.5 mg/kg/day (≥4x MRHD exposure)
“An increased incidence of cardiac ventricular septal defect along with truncus arteriosus communis was observed at ≥2.5 mg/kg/day, which is ≥4 times the human exposure at the MRHD.”
Safety pharmacology
Dog telemetry: PR interval effect with heart-rate change, possible QRS effect, no QT/QTc effect
“The cardiovascular safety pharmacology in telemetered dogs indicated an effect on the PR interval concurrent with a change in heart rate, possibly an effect on the QRS complex but no effect on QT/QTc intervals.”
Genotox: Ames
Negative (Ames)
“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”
Genotox: in vivo
Rat and mouse micronucleus: negative
“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”
Carcinogenicity model
2-year CD1 mouse and 2-year Wistar rat
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
Carcinogenicity timing
2-year CD1 mouse and Wistar rat studies completed before the marketing application
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
hERG / QT
hERG IC50 ~10 µM, 546-fold margin; assay deviated from ICH S7B Q&A best practices
“A suboptimal in vitro assay showed the parent drug to be a moderate inhibitor of the hERG channel with an IC50 of 10µM. Although the safety margin of vericiguat on hERG current is high (546-fold), the hERG assay deviates significantly from the new ICH S7B Q&A best practices.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Verquvo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Consistent target organs: liver, kidney and adrenals (FDA integrated review, p. 146)
NOAEL / key findings
Consistent target organs: liver, kidney and adrenals
“Consistent target organs of toxicity were the liver, kidney, and adrenals.”
Risksopen answer page →
Immune & cytokine safety
No indicators of immune-system effects; no further immunotoxicity evaluation
“As there were no indicators of effects on the immune system, no further specific evaluation was conducted.”
Biodistribution & persistence
Melanin binding, including substantia nigra, with longer half-lives in melanin-containing tissues
“Melanin binding of vericiguat and/or its metabolites was also observed for the substantia nigra. Elimination occurred with longer terminal half-lives in melanin-containing tissues”
Modality-specific risk
Embryo-fetal toxicity, possibly a sGC-stimulator class effect
“An additional risk of embryo-fetal toxicity was identified based on findings in rats and rabbits. This risk may be related to the pharmacologic class, as similar findings have been observed with another soluble guanylate cyclase (sGC) stimulator”
Anti-drug antibodies: animals
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Anti-drug antibodies: patients
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Label warnings
Boxed warning: Embryo-fetal toxicity
- Embryo-Fetal Toxicity
Embryo-fetal toxicity
US prescribing information, Boxed Warning and Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Verquvo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Consistent target organs: liver, kidney and adrenals (FDA integrated review, p. 146)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week dog; recovery phase not described
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Pivotal GLP studies
6-month rat and 39-week dog oral GLP studies
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal, juvenile) and rabbit (EFD)
“in reproductive and developmental toxicity studies (including embryo-fetal development studies in rats and rabbits, fertility and early embryonic development and a pre- and postnatal development study in rats, and juvenile toxicity studies in rats)”
Reproductive & developmental
Rabbit EFD: cardiac ventricular septal defect and truncus arteriosus at ≥2.5 mg/kg/day (≥4x MRHD exposure)
“An increased incidence of cardiac ventricular septal defect along with truncus arteriosus communis was observed at ≥2.5 mg/kg/day, which is ≥4 times the human exposure at the MRHD.”
PPND / ePPND: when
Rat PPND completed and reviewed in the NDA
“In a pre-postnatal development study in rats, vericiguat was administered orally at doses of 7.5, 15 or 30 mg/kg/day from GD 6 through lactation day 21.”
Carcinogenicity
Species: carcinogenicity
CD1 mouse and Wistar rat (2-year)
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
Carcinogenicity model
2-year CD1 mouse and 2-year Wistar rat
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
Carcinogenicity timing
2-year CD1 mouse and Wistar rat studies completed before the marketing application
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month dog NOAEL 5 mg/kg: 2.4x human AUC at MRHD
“9-month dog 5 Combined 16000 2.4X NOAEL = no observed adverse effect level”
NOAEL / key findings
Consistent target organs: liver, kidney and adrenals
“Consistent target organs of toxicity were the liver, kidney, and adrenals.”
Efficacy evidenceopen answer page →
Efficacy evidence
Spontaneously hypertensive rats, renin-transgenic rat heart failure model, dog/minipig PAH and dog PH-LVD models
“in vivo pharmacodynamic studies were conducted in healthy rats and dogs, spontaneous hypertensive rats (SHR), a hypertension and heart failure model (renin-transgenic rats), a dog and minipig model of pulmonary arterial hypertension (PAH), and a dog model of pulmonary hypertension secondary to left ventricular dysfunction (PH-LVD).”
Why that model
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reviewer's view of the efficacy data
EMA: in vivo pharmacodynamic effects consistent with the sGC-stimulating mechanism (vasodilatation)
“Taken together, the pharmacodynamic effect seen in the in vivo studies with vericiguat is consistent with its mechanism of action, i.e. stimulation of the NO-sGC-cGMP pathway, leading to vasodilatation.”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyCriticised but acceptedBeyond the letter
In vitro hERG assay deviated from ICH S7B Q&A best practices (voltage protocol, no concentration verification or positive controls)
Why: Additional CiPA-based ion channel studies submitted during review showed no proarrhythmic channel interactions · Weight of evidence
“Although the safety margin of vericiguat on hERG current is high (546-fold), the hERG assay deviates significantly from the new ICH S7B Q&A best practices. Specifically, the study used a different voltage protocol, lacked concentration verification and positive controls”
“The applicant submitted the results of these studies on November 18, 2020. Overall, these channel studies also showed no evidence of membrane channel interactions with vericiguat exposure that would result in proarrhythmia.”
Impurity or metaboliteAcceptedBeyond the letter
Major human metabolite M1 (70% of human plasma exposure) below 0.24x human AUC in rodent carcinogenicity studies; not separately dosed
Why: Administered M1 unlikely to remain intact through the stomach, so dosing it would add little · Pharmacology or kinetics
“This is an N-glucuronide that accounts for 70% of human plasma exposure and in rat and mouse accounts for less than 10% of total exposure, reaching <0.24X the human AUC.”
“The Executive CAC determined that if the M1 metabolite was synthesized and administered, it was not likely to remain intact during passage through the stomach. Therefore, additional synthesis and administration of the compound was not likely to add to the informative value of the studies.”
Juvenile toxAccepted with a conditionBeyond the letter
Juvenile rat developmental toxicity study (bone effects) deferred to a postmarketing requirement
Why: Bone effects not expected in the adult heart failure population · Human data
“A non-clinical PMR will be issued to evaluate developmental toxicity in juvenile rats in order to support dosing for potential studies in a pediatric population.”
“Conclusion: Bone effects were not observed in VICTORIA and were not expected given the age of the patient population.”
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